It is the overall objective of this research program to develop efficient synthetic procedures for the construction of cyclopentenone, alpha-methylene cyclopentenone and latent alpha-methylene cyclopentenone antibiotics which appear to have significant potential as antitumor agents. As synthetic targets in this area we have chosen A) xanthocidin B) quadrone and C) the epi-pentenomycins (antibiotics C-2554-AI, AII and B). Xanthocidin and the epi-pentenomycins are structurally very similar to the antibiotic sarkomycin known to possess significant antitumor activity. Quadrone, on the other hand, is known to display significant inhibitory activity against human epidermoid carcinoma of the nasopharynx (KB) and presumptive activity in vitro against P 388 lymphocytic leukemia in mice. Finally, we plan to explore the synthons available via the alpha-ketovinyl anion equivalent methodology developed in connection with our pentenomycin total synthesis which was carried out under the auspicies of our current NIH-NCI grant (CA-19033). A more general underlying and long range objective of this research program is the development of a better understanding of the molecular architecture responsible for the antitumor properties of these and related systems. Thus, as we develop our method of procedure for each of the above synthetic targets, we will introduce various model systems which will be amenable to synthesis and subsequent testing by the Drug Research and Development Division of the NCI, such that in the end we will be able to disect out the critical structural features responsible for the observed antitumor properties. Once such features are identified the design of new and possibly more effective antitumor drugs should be feasible. (This application is a renewal proposal for our current NIH-NCI grant CA-19033).